Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug.

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan.

A novel, differential mobility spectrometry tandem mass spectrometric method for the in vivo quantitation of ursolic acid.

Ursolic acid (UA) is a naturally occurring pentacyclic triterpene widely distributed in fruits and plants. It is pharmacologically active and has the potential to be a useful therapeutic compound. To date, bioanalysis of UA has been limited by biomatrix interference and poor collision induced dissociation (CID) efficiency in tandem mass spectrometry.

The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)--poly(d,l-lactic acid) in rat.

Monomethoxy poly(ethylene glycol)--poly(d,l-lactic acid) (PEG-PLA) is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier (nanocarrier) in drug delivery. Understanding the fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery systems. However, acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of PEG-PLA.

Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein.

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation , PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed.

Comprehensive Bioanalysis of Ultrahigh Molecular Weight, Highly Disperse Poly(ethylene oxide) in Rat via Microsolid Phase Extraction and RPLC-Q-Q-TOF Coupled with the MS Technique.

Ultrahigh molecular weight (UHMW) poly(ethylene oxide) (PEO) is a synthetic hydrophilic polymer with wide dispersity which shows considerable promise as a hemostatic agent in the treatment of gastrointestinal bleeding. Currently there is no analytical method for the determination of highly disperse UHMW PEO in biological samples that would allow its characterization in vivo and support its clinical development. Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful bioanalytical tool, it faces major challenges when applied to UHMW PEO.

Liquid chromatography tandem mass spectrometry with triple stage fragmentation for highly selective analysis and pharmacokinetics of alarelin in rat plasma.

Alarelin, a gonadotropin-releasing hormone analogue, is widely used in China for the treatment of endometriosis and uterine leiomyoma. In order to investigate its pharmacokinetic behavior and support the preclinical application of new formulations, we have developed a novel and highly selective bioanalytical method to determine alarelin in rat plasma based on liquid chromatography tandem mass spectrometry with triple stage fragmentation. After sample preparation by protein precipitation followed by reversed phase solid phase extraction, alarelin and triptorelin (internal standard) were chromatographed on an Ascentis Express C18 column (50 mm × 4.

Absorption, distribution, metabolism and excretion of the biomaterials used in Nanocarrier drug delivery systems.

Nanocarriers (NCs) are a type of drug delivery system commonly used to regulate the pharmacokinetic and pharmacodynamic properties of drugs. Although a wide variety of NCs has been developed, relatively few have been registered for clinical trials and even fewer are clinically approved. Overt or potential toxicity, indistinct mechanisms of drug release and unsatisfactory pharmacokinetic behavior all contribute to their high failure rate during preclinical and clinical testing.

Development and application of a high-throughput liquid chromatography-tandem mass spectrometric method for the simultaneous determination of thymosin α1 and its recombinant human form in plasma and urine.

Thymosin α1 (Thymalfasin, Tα1) is a naturally occurring polypeptide widely used as an immune system enhancer for the treatment of HIV/AIDS, hepatitis B and C, and cancer. Recombinant human Tα1 (rh-Tα1) lacking N-terminal acetylation (NTA) displays similar biological activity to Tα1 and has completed phase III clinical trials in China. To compare the pharmacokinetics of rh-Tα1 and Tα1 and establish whether they undergo mutual transmutation in vivo, we developed a novel bioassay based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of the two peptides in human plasma and urine.

Micro-solid phase extraction and LC-MS for the determination of triptorelin in rat plasma and application to a pharmacokinetic study.

Triptorelin is a synthetic decapeptide used for the treatment of prostate cancer. Attempts to determine triptorelin in clinical use by liquid chromatography-tandem mass spectrometry with multiple reaction monitoring have encountered problems due to its low concentration in plasma (pg/mL) and interference from endogenous peptides. We have overcome these issues using micro-solid phase extraction (μ-SPE) on Oasis® HLB 96-well μElution plates followed by LC-MS.

A Unique Collision-Induced Dissociation Reaction of Cholamine Derivatives of Certain Prostaglandins.

Prostaglandins (PGs) are biologically active metabolites of arachidonic acid containing 20 carbon atoms, a cyclic moiety, and two side chains (A and B) in common. The bioassay of PGs requires high sensitivity because of their low concentration in tissues and blood and has usually been carried out by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative ion mode. Chemical derivatization of PG carboxylic acid groups to introduce positive charge-carrying groups is an established strategy to improve the sensitivity and selectivity of such assays.

Bioanalysis of free and liposomal Amphotericin B in rat plasma using solid phase extraction and protein precipitation followed by LC-MS/MS.

Amphotericin B (AMB) is a polyene macrolide antibiotic used for treating invasive fungal infections. Liposomal AMB (L-AMB) is a lipid dosage form which reduces the side effects and toxicity of the drug. The quantitation of free AMB (F-AMB) and L-AMB in vivo is important to monitor quality control of the liposomal formulation and to ensure its safety during clinical use.

Establishment of a Charge Reversal Derivatization Strategy to Improve the Ionization Efficiency of Limaprost and Investigation of the Fragmentation Patterns of Limaprost Derivatives Via Exclusive Neutral Loss and Survival Yield Method.

Sensitivity is generally an issue in bioassays of prostaglandins and their synthetic analogs due to their extremely low concentration in vivo. To improve the ionization efficiency of limaprost, an oral prostaglandin E1 (PGE1) synthetic analog, we investigated a charge reversal derivatization strategy in electrospray ionization mass spectrometry (ESI-MS). We established that the cholamine derivative exhibits much greater signal intensity in the positive-ion mode compared with limaprost in the negative ion mode.

A validated UPLC-MS/MS method coupled with protein precipitation and ion exchange solid phase extraction for the quantitation of porcine relaxin B29 in dog plasma and its application to a pharmacokinetic study.

Porcine relaxin is a 6 kDa peptide hormone of pregnancy with important physiological and pharmacological effects. It contains a number of analogs of which porcine relaxin B29 is one of the most important. To support the development of porcine relaxin B29 as a new drug, we established an UPLC-MS/MS method for its quantitation in dog plasma.

Differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring for the bioanalysis of liraglutide.

Liraglutide is a glucagon-like peptide-1 analog for the treatment of type 2 diabetes. Major interference in plasma of human and animals and low fragment signal in tandem mass spectrometry are the main difficulties encountered in the bioanalysis of liraglutide. In this study, by combining differential mobility spectrometry (DMS) with multiple ion monitoring detection (MIM), a liquid chromatography differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring detection (LC-DMS-MIM) method was developed for the quantitation of liraglutide in dog plasma.

Development and Application of an MS-Based Approach for the Quantitative Analysis of Linear Polyethylene Glycols in Rat Plasma by Liquid Chromatography Triple-Quadrupole/Time-of-Flight Mass Spectrometry.

Polyethylene glycols (PEGs) are synthetic polymers composed of repeating ethylene oxide subunits. They display excellent biocompatibility and are widely used as pharmaceutical excipients. To fully understand the biological fate of PEGs requires accurate and sensitive analytical methods for their quantitation.

Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration.

In the search for prodrug analogs of clopidogrel with improved metabolic characteristics and antiplatelet bioactivity, a group of clopidogrel and vicagrel analogs selectively deuterated at the benzylic methyl ester group were synthesized, characterized, and evaluated. The compounds included clopidogrel-d₃ (8), 2-oxoclopidogrel-d₃ (9), vicagrel-d₃ (10a), and 12 vicagrel-d₃ analogs (10b-10m) with different alkyl groups in the thiophene ester moiety. The D₃C-O bond length in 10a was shown by X-ray single crystal diffraction to be shorter than the H₃C-O bond length in clopidogrel, consistent with the slower rate of hydrolysis of 8 than of clopidogrel in rat whole blood in vitro.

Development and validation of an enantioselective SFC-MS/MS method for simultaneous separation and quantification of oxcarbazepine and its chiral metabolites in beagle dog plasma.

A rapid and sensitive assay based on supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) has been developed and validated for the determination of oxcarbazepine (OXC) and its chiral metabolite licarbazine (Lic) in beagle dog plasma using carbamazepine as internal standard. Chiral analysis in a run time of only 3 min was performed on an ACQUITY UPC(2) ™ Trefoil™ CEL2 column (3.0 × 150 mm, 2.

Trantinterol, a novel β2-adrenoceptor agonist, noncompetitively inhibits P-glycoprotein function in vitro and in vivo.

P-glycoprotein (P-gp)-mediated drug-drug interactions are important factors causing adverse effects of drugs in clinical use. The aim of this study was to determine whether trantinterol (also known as SPFF), a novel β2-adrenoceptor agonist, was a P-gp inhibitor or substrate. The results showed that trantinterol was not a substrate of P-gp but increased rhodamine 123 (Rho 123) uptake by MDCK-MDR1 cells and decreased the efflux transport of both Rho 123 and cyclosporine A (CsA) in bidirectional transport studies across MDCK-MDR1 cell monolayers.

Acarbose bioequivalence: exploration of new pharmacodynamic parameters.

To investigate bioequivalence (BE) testing of an acarbose formulation in healthy Chinese volunteers through the use of recommended and innovative pharmacodynamic (PD) parameters. Following the Food and Drug Administration (FDA) guidance, a randomized, cross-over study of acarbose test (T) and reference (R) (Glucobay®) formulations was performed with a 1-week wash-out period. Preliminary pilot studies showed that the appropriate dose of acarbose was 2 × 50 mg, and the required number of subjects was 40.

Rapid and sensitive assay for trantinterol, a novel beta(2)-adrenoceptor agonist, in human plasma using liquid chromatography-tandem mass spectrometry.

A rapid and sensitive assay for trantinterol, a novel beta(2)-adrenoceptor agonist, in human plasma has been developed. Samples containing the analyte and internal standard, clenbuterol, were analyzed by liquid chromatography-tandem mass spectrometry after liquid-liquid extraction with diethyl ether:dichloromethane (60:40, v/v). Separation was performed on a Venusil MP C(18) column (50 mm x 4.

Characterization of the pharmacokinetics of dioscin in rat.

Dioscin (diosgenyl 2,4-di-O-alpha-l-rhamnopyranosyl-beta-d-glucopyranoside) is an important constituent of some traditional Chinese medicines with several bioactivities. We have investigated the pharmacokinetics of dioscin in rat after intravenous and oral administrations. Compartmental methods were used to perform pharmacokinetic data analysis.

Decrease in hepatic drug-metabolizing enzyme activities after removal of rats from pine bedding.

Wood is often used as a contact bedding material for laboratory animals. It has been established that wood, particularly softwood, has the potential to induce hepatic drug-metabolizing enzymes. However, to the authors' knowledge, changes in enzyme activity after removal of animals from bedding have not been characterized.